1. Field of the Invention
The present invention relates to a novel cystine derivative and a method for producing the same, a composition for suppressing the activation of inflammatory factors, which is useful for the prevention, amelioration and/or therapeutic treatment of diseases related to inflammatory factors, such as diseases involved in the activation of inflammatory factors and inflammatory diseases (disorders) or dermal damages based on the activation and which contains the novel derivative as an effective ingredient. The present invention also relates to a method for suppressing the activation of inflammatory factor using a composition containing the novel cystine derivatives for suppressing the activation of inflammatory factors.
In more specific aspects of the composition for suppressing the activation of inflammatory factors, the invention relates to pharmaceutical agents (pharmaceutical products), particularly external skin application agents, eye drops, nutrition agents, transfusion or the like, cosmetics (including additives for cosmetics), foods or drinks (health foods or drinks or the like), and the like, which contain the cystine derivative with the action to suppress the activation of inflammatory factors as the effective ingredient.
Additionally, the invention relates to a method for suppressing the activation of inflammatory factors, a use of the specific active ingredient thereof (the effective ingredient described above) for the composition for suppressing the activation of inflammatory factors, and the like.
2. Discussion of the Background
In recent years, intensive investigations have been focused on examining the pathogenesis of various diseases and dermal damages caused by the activation of inflammatory factors induced by ultraviolet ray and by oxidative stress with active oxygen, free radicals, and various psychological stress. It has been determined that iron released from proteins (transferrin, lactoferrin, ferritin and the like) in biological organisms via oxidative stress functions as a catalyst to promote the generation of free radical (the Fenton reaction) (see for example Journal of Investigative Dermatology, Vol. 97, 1991, pp. 1044-1047). Additionally, it has also been determined that inflammatory cytokines such as IL-1α and TNF-α and extracellular matrix decomposition enzymes, such as collagenase, are deeply involved causatively in aging, oncogenesis, pigmentation, inflammation and the like (see for example “Oxidative Stress in Dermatology”, Marcel Dekker, Inc., pp. 187-205, 1993).
The expression of genes encoding the aforementioned proteins is mainly regulated at the transcription level of the genes. With respect to inflammatory proteins (such as inflammatory cytokines and extracellular matrix decomposition enzymes) transcription regulators or regulatory factors (such as NF-κB and AP-1) regulate the expression thereof (see for example “Active Oxygen and Signal Transmission”, Kodansha Scientific, pp. 37-46, 1996). Therefore; it is hypothesized that oxidative stress may be reduced and/or diseases and damages involved in the activation of inflammatory factors may be prevented, when the generation of free radical can be suppressed via the capture of released iron ion involved in the promotion of the generation of free radical and/or when the expression of inflammatory proteins and the activation of transcription regulators involved therein can be suppressed.
In the past, it has been discovered that amino acid derivatives for example N-(2-hydroxybenzyl)-L-serine and N-(2-hydroxybenzyl)-glycine (see for example Biochimica et Biophysica Acta, Vol. 1473, 1999, pp. 400-408; and U.S. Pat. No. 5,594,012) and chelators such as desferrioxamine (see for example Free Radical Research, Vol. 20, 1994, pp. 83-101) capture iron ion to reduce oxidative stress. Further, it has been discovered that sulfur-containing anti-oxidants, such as N-acetyl-L-cysteine, N,N′-diacetyl-L-cystine dimethyl ester and pyrrolidine dithiocarbamate, suppress the activation of NF-κB (see for example “Active Oxygen and Signal Transmission”, Kodansha Scientific, pp. 37-46, 1996; and WO 00/21925). It has also been reported that N-acetyl-L-cysteine and N,N′-diacetyl-L-cystine dimethyl ester also suppress the activation of AP-1 (see for example FEBS Letters, Vol. 384, pp. 92-96, 1996; and WO 00/21925).
However, disadvantageously, the aforementioned compounds have proven to have insufficient in vivo effes and desferrioxamine, pyrrolidine dithiocarbamate, and the like, have strong toxicity on cells. Other than chelators and sulfur-containing anti-oxidants, for example, reports demonstrate that retinoic acid activates AP-1 and suppresses the expression of extracellular matrix decomposition enzymes (see for example Nature, Vol. 379, pp. 335-339, 1996) and that steroidal anti-inflammatory agents or non-steroidal anti-inflammatory agents suppress the activation of NF-κB (see for example Bio Assays, Vol. 18, pp. 371-378, 1996). However, retinoic acid and steroidal anti-inflammatory agents have adverse effects in vivo such as dermal detachment and steroidal dermatitis, respectively. Therefore, the use thereof is limited. Non-steroidal anti-inflammatory agents still remain to be improved of their local adverse effects and have insufficient effects on the suppression of the activation of inflammatory factors, although non-steroidal anti-inflammatory agents have no systemic adverse effects caused by steroidal anti-inflammatory agents.
Skin change via aging or aesthetically unfavorable skin changes are disorders, dermal damages, and/or diseases caused by the activation of inflammatory factors. A method for preventing or delaying such a change has been reported. This method entails coating a combination of natural extracts with an action to ameliorate rough skin and the like, such as astaxanthin or ingredients contained therein, with cystine derivatives on skin (see for example Japanese Patent Kokai Publication JP-A-9-143063). This combination can enhance the recovery of tension or luster of skin or can ameliorate the darkness of skin, but the effect thereof is not sufficient. Additionally, the effect thereof on the most prominent skin wrinkle or looseness among senile skin findings has not been demonstrated.
The induction or promotion of skin wrinkles or looseness is a representative example of the skin change via aging or aesthetically unfavorable skin change caused by the activation of inflammatory factors, which are induced via oxidative or psychological stresses. The cause of these stresses includes sunlight, ultraviolet ray in sunlight or ultraviolet ray in other light sources (see for example “New Cosmetology”, Nanzando, pp. 38-46, 1993). A method for preventing or delaying these phenomena has been reported and entails coating an anti-oxidant, such as tocopherol, ascorbic acid or N-acetyl-L-cystine on skin (see for example Photodermatol. Photoimmunol. Photomed., Vol. 7, pp. 56-62, 1990; and Japanese Patent Kohyo Publication JP-A-6-510542). In addition to anti-oxidants, some anti-inflammation agents or ultraviolet absorbents have been demonstrated to have effects on the prevention or delay of induction or promotion of skin wrinkles or looseness (see for example Photodermatol. Photoimmunol. Photomed., Vol. 7, pp. 153-158, 1990; and J. Photochem. Photobiol. B: Biol., Vol. 9, pp. 323-334, 1991), while retinoic acid can ameliorate such phenomena (see for example J. Invest. Dermatol., Vol.98, pp. 248-254, 1992). However, disadvantageously, these compounds have insufficient effects in vivo, have strong cellular toxicity, or low optical stability. Further, anti-inflammatory agents and retinoic acids also share these adverse effects.
Accordingly, there remains a critical need for the development of an agent for suppressing the activation of inflammatory factor(s), which is particularly great in view of pharmacological activity and safety profile.